Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis

Parra, Valentina; Eisner, Verónica; Chiong, Mario; Criollo, Alfredo; Moraga, Francisco; García, Alejandra; Härtel, Steffen; Jaimovich, Enrique; Zorzano, António; Hidalgo, Cecilia; Lavandero, Sergio

doi:10.1093/cvr/cvm029

Cited by 219 publications

(194 citation statements)

References 51 publications

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“…Thus, BAK may induce BAX activation and apoptosis in part through ceramide generation. Ceramide has been implicated in both components of MOMP induction, namely mitochondrial fragmentation (43,44) and formation of a pore in the mitochondrial outer membrane (17,26,27,46). Thus, the data presented herein now point to a model where a BAK-mediated increase in ceramide facilitates MOMP induction via mitochondrial fragmentation and pore formation, leading to cytochrome c release, caspase activation, and the execution phase of apoptosis.…”

Section: Discussionmentioning

confidence: 57%

“…Here we describe a second unique function for BAK in apoptosis, namely regulation of ceramide generation. Intriguingly, ceramides can also cause mitochondrial fragmentation (43,44). Furthermore, ceramides induce negative curvature and lateral phase separation in giant liposomes leading to their fragmentation (45).…”

Section: Discussionmentioning

confidence: 99%

“…Ceramide can activate BAX during apoptosis (26,27), and in some systems BAX activation is dependent upon the presence of BAK (44). Thus, BAK may induce BAX activation and apoptosis in part through ceramide generation.…”

Section: Discussionmentioning

confidence: 99%

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The BCL-2 Protein BAK Is Required for Long-chain Ceramide Generation during Apoptosis

Siskind

Mullen

Rosales

et al. 2010

Journal of Biological Chemistry

113

103

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The BCL-2 family members BAK and BAX are required for apoptosis and trigger mitochondrial outer membrane permeabilization (MOMP). Here we identify a MOMP-independent function of BAK as a required factor for long-chain ceramide production in response to pro-apoptotic stress. UV-C irradiation of wild-type (WT) cells increased long-chain ceramides; blocking ceramide generation prevented caspase activation and cell death, demonstrating that long-chain ceramides play a key role in UV-C-induced apoptosis. In contrast, UV-C irradiation did not increase long-chain ceramides in BAK and BAX double knock-out cells. Notably, this was not specific to the cell type (baby mouse kidney cells, hematopoietic) nor the apoptotic stimulus employed (UV-C, cisplatin, and growth factor withdrawal). Importantly, long-chain ceramide generation was dependent on the presence of BAK, but not BAX. However, ceramide generation was independent of the known downstream actions of BAK in apoptosis (MOMP or caspase activation), suggesting a novel role for BAK in apoptosis. Finally, enzymatic assays identified ceramide synthase as the mechanism by which BAK regulates ceramide metabolism. There was no change in CerS expression at the message or protein level, indicating regulation at the post-translational level. Moreover, CerS activity in BAK KO microsomes can be reactivated upon addition of BAKcontaining microsomes. The data presented indicate that ceramide-induced apoptosis is dependent upon BAK and identify a novel role for BAK during apoptosis. By establishing a unique role for BAK in long-chain ceramide metabolism, these studies further demonstrate that the seemingly redundant proteins BAK and BAX have distinct mechanisms of action during apoptosis induction.Programmed cell death (apoptosis) is a complex, multistep process essential for normal tissue homeostasis and development. A key event in apoptotic signaling is mitochondrial outer membrane permeabilization (MOMP), 3 whereby pro-apoptotic factors are released from the mitochondrial intermembrane space into the cytosol resulting in the activation of caspases and triggering the execution phase of apoptosis. Multiple cell death pathways converge on MOMP, and it is considered a necessary step for the commitment of cells to apoptosis. Anti-apoptotic BCL-2 proteins like BCL-2 and BCL-X L can block MOMP and cell death when overexpressed. On the other hand, the proapoptotic BCL-2 proteins BAK and BAX are necessary for MOMP in response to a wide variety of death-inducing signals. In fact, cells lacking both BAK and BAX are highly resistant to apoptotic stimuli (1-4).Sphingolipids have been extensively implicated in the apoptotic response. Ceramide, a central molecule of sphingolipid metabolism, has been shown to be involved in programmed cell death through several lines of evidence. First, cellular levels of ceramide are elevated by a variety of apoptotic stimuli. Second, blocking ceramide generation delays or abrogates cell death in response to many different signals (5-9). Moreover, cancer cells ...

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The BCL-2 Protein BAK Is Required for Long-chain Ceramide Generation during Apoptosis

Siskind

Mullen

Rosales

et al. 2010

Journal of Biological Chemistry

113

103

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“…The tubular mitochondria change into small and round ones during apoptosis (Frank et al, 2001). Concomitantly, Drp1 and hFis1 levels are elevated in early apoptosis in cultured cardiomyocytes (Parra et al, 2008;Ong et al, 2010) and in heart failure model as well (Chen et al, 2009). Drp1 (Frank et al, 2001;Lee et al, 2004) and hFis1 (Lee et al, 2004;Alirol et al, 2006) participate in the process of cell death.…”

Section: Mitochondria Mediate Apoptosis In Heartmentioning

confidence: 98%

Mitochondrial network in the heart

Zhou

Gao

et al. 2012

Protein Cell

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Mitochondria are subcellular organelles that provide energy for the cell. They form a dynamic tubular network and play an important role in maintaining the cell function and integrity. Heart is a powerful organ that supplies the motivation for circulation, thereby requiring large amounts of energy. Thus, the healthiness of cardiomyocytes and mitochondria is necessary for the normal cardiac function. Mitochondria not only lie in the center of the cell apoptotic pathway, but also are the major source of reactive oxygen species (ROS) generation. Mitochondrial morphological change includes fission and fusion that are regulated by a large number of proteins. In this review we discuss the regulators of mitochondrial fission/fusion and their association with cell apoptosis, autophagy and ROS production in the heart.

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“…In addition to steadystate activity, Drp1 is also associated with early apoptosis (4,(7)(8)(9)(10). Cellular stress increases Drp1 shuttling, which leads to fragmented mitochondrial networks, whereas prolonged or severe insult promotes stabilization of Drp1 to the mitochondria, which increases the likelihood of progression to apoptotic cell death (7,8,(11)(12)(13). Phosphorylation of Drp1-S637 prevents translocation to mitochondria, whereas overexpression of Drp1 K38A (a dominant-negative mutation lacking GTPase activity) prevents Drp1 translocation, attenuates a fragmented mitochondrial phenotype, and decreases cell death (4,14).…”

mentioning

confidence: 99%

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Din

Mason

Völkers

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

116

121

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Mitochondrial morphological dynamics affect the outcome of ischemic heart damage and pathogenesis. Recently, mitochondrial fission protein dynamin-related protein 1 (Drp1) has been identified as a mediator of mitochondrial morphological changes and cell death during cardiac ischemic injury. In this study, we report a unique relationship between Pim-1 activity and Drp1 regulation of mitochondrial morphology in cardiomyocytes challenged by ischemic stress. Transgenic hearts overexpressing cardiac Pim-1 display reduction of total Drp1 protein levels, increased phosphorylation of Drp1-S637 , and inhibition of Drp1 localization to the mitochondria. Consistent with these findings, adenoviral-induced Pim-1 neonatal rat cardiomyocytes (NRCMs) retain a reticular mitochondrial phenotype after simulated ischemia (sI) and decreased Drp1 mitochondrial sequestration. Interestingly, adenovirus Pimdominant negative NRCMs show increased expression of Bcl-2 homology 3 (BH3)-only protein p53 up-regulated modulator of apoptosis (PUMA), which has been previously shown to induce Drp1 accumulation at mitochondria and increase sensitivity to apoptotic stimuli. Overexpression of the p53 up-regulated modulator of apoptosis-dominant negative adenovirus attenuates localization of Drp1 to mitochondria in adenovirus Pim-dominant negative NRCMs promotes reticular mitochondrial morphology and inhibits cell death during sI. Therefore, Pim-1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology in response to sI.

show abstract

Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis

Abstract: Ceramides stimulate mitochondrial fission and this event is associated with early activation of cardiomyocyte apoptosis.

Cited by 219 publications

References 51 publications

The BCL-2 Protein BAK Is Required for Long-chain Ceramide Generation during Apoptosis

The BCL-2 Protein BAK Is Required for Long-chain Ceramide Generation during Apoptosis

Mitochondrial network in the heart

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

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